The early diagnosis of malignant tumor diseases plays an important role in the survival prognosis of a tumor patient. For this diagnosis, non-invasive diagnostic imaging methods are an important aid. In the last years, in particular the PET (Positron Emission Tomography) technology has been found to be particularly useful. The sensitivity and specificity of the PET technology depends essentially on the signal-giving substance (tracer) used and on its distribution in the body. In the hunt for suitable traces, one tries to make use of certain properties of tumors which differentiate tumor tissue from healthy surrounding tissue. The preferred commercial isotope used for PET applications is 18F. Owing to the short half-life of less than 2 hours, 18F is particularly demanding when it comes to the preparation of suitable tracers. This isotope does not allow complicated long synthesis routes and purification procedures, since otherwise a considerable amount of the radioactivity of the isotope will already have decayed before the tracer can be used for diagnosis. Therefore, often it is not possible to apply established synthesis routes for non-radioactive fluorinations to the synthesis of 18F tracers. Furthermore, the high specific activity of 18F (about 80 GBq/nmol) leads to very low substance amounts of [18F]fluoride for the tracer synthesis, which in turn requires an extreme excess of precursor, making the result of a radio synthesis strategy based on a non-radioactive fluorination reaction unpredictable.
FDG ([18F]-2-Fluorodeoxyglucose)-PET is a widely accepted and frequently used auxiliary in the diagnosis and further clinical monitoring of tumor disorders. Malignant tumors compete with the host organism for glucose as nutrient supply (Warburg O., Über den Stoffwechsel der Carcinomzelle [The metabolism of the carcinoma cell], Biochem. Zeitschrift 1924; 152: 309-339; Kellof G., Progress and Promise of FDG-PET Imaging for Cancer Patient Management and Oncologic Drug Development, Clin. Cancer Res. 2005; 11(8): 2785-2807). Compared to the surrounding cells of the normal tissue, tumor cells usually have an increased glucose metabolism. This is exploited when using fluorodeoxyglucose (FDG), a glucose derivative which is increasingly transported into the cells, where, however, it is metabolically captured as FDG 6-phosphate after phosphorylation (“Warburg effect”). Accordingly, 18F-labeled FDG is an effective tracer for detecting tumor disorders in patients using the PET technology. In the hunt for novel PET tracers, recently, amino acids have been employed increasingly for 18F PET imaging (for example (review): Eur. J. Nucl. Med. Mol. Imaging. May 2002; 29(5): 681-90). Here, some of the 18F-labeled amino acids are suitable for measuring the rate of protein synthesis, but most other derivatives are suitable for measuring the direct cellular uptake in the tumor. Known 18F-labeled amino acids are derived, for example, from tyrosine amino acids, phenylalanine amino acids, proline amino acids, asparagine amino acids and unnatural amino acids (for example J. Nucl. Med. 1991; 32: 1338-1346, J. Nucl. Med. 1996; 37: 320-325, J. Nucl. Med. 2001; 42: 752-754 and J. Nucl. Med. 1999; 40: 331-338).
Recently, the use and the synthesis of 18F/19F-labeled glutamic acid derivatives and glutamine derivatives has been published (WO2008052788, WO2009141091). Compounds with very promising preclinical results (WO2008052788, J. Med. Chem. 2011; (54):406-410, J Nucl Med. 2010; 51 (Supplement 2):1535) were tested in first clinical studies. For [18F]-4-fluoro-glutamic acid good tumor uptake was found. However, some defluorination was detected which negatively influenced the tumor-background-ratio. (J Nucl Med. 2010; 51 (Supplement 2):118). Superior results were obtained applying (S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid in first clinical studies. Very good results were found in the detection of lung cancer (Koglin et al., Abstract Nr. 412, SNM 2011, San Antonio; Baek et al., Abstract Nr. 195, SNM 2011, San Antonio).
Common leaving groups for labeling in alkyl positions described in the literature are sulfonates such as mesylate, tosylate, and triflate or halides (Ernst Schering Res Found Workshop. 2007; (62):15-50 and Eur. J. Org. Chem. 2008, 2853-2873).
Novel leaving groups with different scopes have been published. Lu et al. describe the use of leaving groups which already contain the phase transfer catalyst for the introduction of the [18F]fluoride (Lu et al. J. Org. Chem. 2009; (74):5290-5296). These leaving groups contain an arylsulfonate and a chelating unit which is attached to the aryl ring via an ether ring.
Furthermore, the use of special leaving groups which support the removal of the precursor in a purification step after the radiolabeling was reported (WO2011006610). The leaving groups described are sulfonates containing a lipophilic part to allow a simple purification.
For the synthesis of 4-(3-[18F]Fluoropropyl)-L-glutamic acid different precursors have been described.
In WO2008052788 and WO2009141091, the precursor is a combination of known amino and carboxyl protecting groups and leaving groups such as of Chloro, Bromo, sulfonate derivatives such as Tosyloxy resulting into a suitable 18F radiolabeling precursor in oily form. WO2010000409 refers to the use of novel perfluorinated precursors, its 18F-radiolabeling and the purification of the resulting compound. These methods were also applied for the manufacture of 4-(3-[18F]Fluoropropyl)-L-glutamic acid.
However, the synthesis of the compound remains challenging. One important factor in the production of the radiotracer is a precursor suitable for 18F radiolabeling. Due to the presence of different functional groups (carboxylic group, amino group) the introduction of protecting groups is necessary for conducting the radiolabeling without loss of functional groups. In addition, the presence of a leaving group is required to enable the nucleophilic introduction of the 18F-label.
Until now, no solid precursor for the synthesis of 4-(3-[18F]Fluoropropyl)-L-glutamic acid has been described.